Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclosporin A (CsA) is a potent inhibitor of the NFAT family of transcription factors that enhance T cell activation. The observation that human immunodeficiency virus type 1 (HIV-1)-positive transplant recipients have a reduced HIV-1 viral burden during treatment with CsA suggested that NFAT may play a direct role in enhancing transcription of the HIV-1 viral genome. Two sets of NFAT binding sites were identified in the HIV-1 long terminal repeat (LTR) promoter by in vitro footprinting with full-length recombinant NFAT protein, and gel shift analysis of nuclear protein from polyclonally activated primary CD4 T cells revealed specific binding of NFAT1 to the NFkappaB binding sites of the HIV-1 LTR. Activation of primary CD4 T cells transiently transfected with a HIV-1 LTR luciferase reporter plasmid, lacking the NFAT binding sites in the upstream putative negative regulatory element but maintaining the NFkappaB/NFAT sites, demonstrated increased HIV-1 gene expression when cotransfected with a NFAT1 expression vector. Moreover, CsA, FK506, and a dominant-negative NFAT1 protein independently inhibited HIV-1 LTR promoter activity in CD4 T cells stimulated with phorbol ester and calcium ionophore. In primary human CD4 T cells, CsA also inhibited promoter activity directed by multimers of binding sites for NFAT, while having no effect on NFkappaB multimer-driven promoter activity. Increasing NFAT1 levels in CD4 T cells transiently transfected with a HIV-1 provirus also increased p24 protein expression. Thus, NFAT may be a target for prevention of HIV-1 LTR-directed gene expression in human CD4 T cells.
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PMID:NFAT1 enhances HIV-1 gene expression in primary human CD4 T cells. 1069 37

Although protein tyrosine phosphatase (PTP) inhibitors used in combination with other stimuli can induce interleukin 2 (IL-2) production in T cells, a direct implication of nuclear factor of activated T cells (NFAT) has not yet been demonstrated. This study reports that exposure of leukemic T cells and human peripheral blood mononuclear cells to bis-peroxovanadium (bpV) PTP inhibitors markedly induce activation and nuclear translocation of NFAT. NFAT activation by bpV was inhibited by the immunosuppressive drugs FK506 and cyclosporin A, as well as by a specific peptide inhibitor of NFAT activation. Mobility shift assays showed specific induction of the NFAT1 member by bpV molecules. The bpV-mediated NFAT activation was observed to be important for the up-regulation of the human immunodeficiency virus 1 (HIV-1) long terminal repeat (LTR) and the IL-2 promoter; NFAT1 was demonstrated to be particularly important in bpV-dependent positive action on HIV-1 LTR transcription. The active participation of p56(lck), ZAP-70, p21(ras), and calcium in the bpV-mediated signaling cascade leading to NFAT activation was confirmed, using deficient cell lines and dominant-negative mutants. Finally, overexpression of wild-type SHP-1 resulted in a greatly diminished activation of NFAT by bpV, suggesting an involvement of SHP-1 in the regulation of NFAT activation. These data were confirmed by constitutive NFAT translocation observed in Jurkat cells stably expressing a dominant-negative version of SHP-1. The study proposes that PTP activity attenuates constitutive kinase activities that otherwise would lead to constant NFAT activation and that this activation is participating in HIV-1 LTR stimulation by PTP inhibition.
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PMID:Regulation of nuclear factor of activated T cells by phosphotyrosyl-specific phosphatase activity: a positive effect on HIV-1 long terminal repeat-driven transcription and a possible implication of SHP-1. 1129 Jun 2

The human immunodeficiency virus-1 (HIV-1), the cause of AIDS, remains a significant cause of morbidity and mortality throughout the planet. Although reverse transcriptase and protease inhibitors have substantially slowed the virus, viral resistance complicates therapy. Because HIV-1 relies on its host's transcriptional machinery for its own replication, strategies for targeting activation-dependent transcription factors in CD4 T cells are being considered for adjunctive therapy in HIV-1-infected individuals. The nuclear factor of activated T cells (NFAT) family of transcription factors is one such target. On T-cell stimulation, NFAT proteins translocate to the nucleus, where they activate a large number of early response genes, including cytokines such as interleukin-2. Activation and nuclear translocation of NFAT proteins are abrogated by the powerful immunosuppressants cyclosporin A (CsA) and FK506. Over the last several years, various investigators have demonstrated that NFAT proteins bind to the HIV-1 LTR promoter and increase viral transcription. In this report, further evidence supporting a role for NFAT proteins in augmenting HIV-1 transcription is presented. In addition, other mechanisms of HIV-1 inhibition by CsA are reviewed, and the rationale for the use of CsA to treat AIDS is discussed.
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PMID:HIV-1, NFAT, and cyclosporin: immunosuppression for the immunosuppressed? 1187 69

The immunosuppressive macrolide rapamycin is used in humans to prevent graft rejection. This drug acts by selectively repressing the translation of proteins that are encoded by an mRNA bearing a 5'-polypyrimidine tract (e.g., ribosomal proteins, elongation factors). The human immunodeficiency virus type 1 (HIV-1) carries a polypyrimidine motif that is located within the tat exon 2. Treatment of human T lymphoid cells with rapamycin resulted in a marked diminution of HIV-1 transcription when infection was performed with luciferase reporter T-tropic and macrophage-tropic viruses. Replication of fully infectious HIV-1 particles was abolished by rapamycin treatment. The rapamycin-mediated inhibitory effect on HIV-1 production was reversed by FK506. The anti-HIV-1 effect of rapamycin was also seen in primary human cells (i.e., peripheral blood lymphocytes) from different healthy donors. Rapamycin was shown to diminish basal HIV-1 long terminal repeat gene expression, and the observed effect of rapamycin on HIV-1 replication seems to be independent of the virus-specific transactivating Tat protein. A constitutive beta-actin promoter-based reporter gene vector was unaffected by rapamycin treatment. Kinetic virus infection studies and exposure to reporter viruses pseudotyped with heterologous envelope proteins (i.e., amphotropic murine leukemia virus and vesicular stomatitis virus G) suggested that rapamycin is primarily affecting the life cycle of HIV-1 at a transcriptional level. Northern blot analysis confirmed that this compound is selectively targeting HIV-1 mRNA synthesis.
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PMID:The immunosuppressant rapamycin represses human immunodeficiency virus type 1 replication. 1238 49

This study explores the role of the calmodulin- and Ca(2+)-sensitive phosphatase calcineurin A in the control of bone resorption by mature osteoclasts. We first cloned full-length calcineurin Aalpha and Abeta cDNA from a rabbit osteoclast library. Sequence analysis revealed an approximately 95 and 86% homology between the amino acid and the nucleotide sequences, respectively, of the two isoforms. The two rabbit isoforms also showed significant homology with the mouse, rat, and human homologs. In situ RT-PCR showed evidence of high levels of expression of calcineurin Aalpha mRNA in freshly isolated rat osteoclasts. Semiquantitative analysis of staining intensity revealed no significant difference in calcineurin Aalpha expression in cells treated with vehicle vs. those treated with the calcineurin (activity) inhibitors cyclosporin A (8 x 10(-7) M) and FK506 (5 x 10(-9) and 5 x 10(-7) M). We then constructed a fusion protein comprising calcineurin Aalpha and TAT, a 12-amino acid-long arginine-rich sequence of the human immunodeficiency virus protein. Others have previously shown that the fusion of proteins to this sequence results in their receptor-less transduction into cells, including osteoclasts. Similarly, unfolding of the TAT-calcineurin Aalpha fusion protein by shocking with 8 M urea resulted in its rapid influx, within minutes, into as many as 90% of all freshly isolated rat osteoclasts, as was evident on double immunostaining with anti-calcineurin Aalpha and anti-TAT antibodies. Pit assays performed with TAT-calcineurin Aalpha-positive osteoclasts revealed a concentration-dependent (10-200 nM) attenuation of bone resorption in the absence of cell cytotoxicity or changes in cell number. TAT-hemaglutinin did not produce significant effects on bone resorption or cell number. The study suggests the following: 1) the 61-kDa protein phosphatase calcineurin Aalpha can be effectively tranduced into osteoclasts by using the TAT-based approach, and 2) the transduced protein retains its capacity to inhibit osteoclastic bone resorption.
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PMID:Molecular cloning, expression, and function of osteoclastic calcineurin Aalpha. 1241 72

Antiretroviral toxic neuropathy is the most common neurological complication of human immunodeficiency virus infection. This painful neuropathy not only affects the quality of life of human immunodeficiency virus-infected patients but also severely limits viral suppression strategies. We have developed an in vitro model of this toxic neuropathy to better understand the mechanism of neurotoxicity and to test potential neuroprotective compounds. We show that among the dideoxynucleosides, ddC appears to be the most neurotoxic, followed by ddI and then d4T. This reflects their potency in causing neuropathy. AZT, which does not cause a peripheral neuropathy in patients, does not cause significant neurotoxicity in our model. Furthermore, in this model, we show that the immunophilin ligand FK506 but not cyclosporin A prevents the development of neurotoxicity by ddC, as judged by amelioration of ddC-induced "neuritic pruning," neuronal mitochondrial depolarization, and neuronal necrotic death. This finding suggests a calcineurin-independent mechanism of neuroprotection. As calcineurin inhibition underlies the immunosuppressive properties of these clinically used immunophilin ligands, this holds promise for the neuroprotective efficacy of nonimmunosuppressive analogs of FK506 in the prevention or treatment of antiretroviral toxic neuropathy.
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PMID:FK506 is neuroprotective in a model of antiretroviral toxic neuropathy. 1250 48

Patients with human immunodeficiency virus (HIV) most often have hepatitis C virus (HCV) or hepatitis B (HBV) virus coinfection, or both, as a cause of their liver disease. Recent survival statistics show that patients infected with HIV treated with highly active antiretroviral therapy (HAART) can expect a significant prolongation of life by interfering with the natural progression of HIV to acquired immune deficiency syndrome (AIDS). Therefore, HIV-positive patients experiencing complications of liver failure are at greater immediate risk of dying from their end-stage liver disease (ESLD) rather than their HIV. Many transplant centers still consider HIV infection as a contraindication for orthotopic liver transplantation (OLT). At our two institutions, we believe that patients with HIV suffering from ESLD should be considered for OLT. This study evaluates the survival of patients undergoing OLT with HIV under HAART therapy. OLT was performed in 16 patients with HIV suffering from ESLD as a result of chronic HCV, chronic HBV, or fulminant hepatic failure (FHF). Collected data include patient demographics, patient and graft survival, pre-OLT assessments, and postoperative complications (including opportunistic infections). Ten patients at Pittsburgh and 6 patients at Miami received OLT. Of the 16 patients who received OLT, 14 remain alive to date. Thirteen of 16 patients are more than 12 months post-OLT, whereas the last patient is currently 6 months post-OLT. Five patients at Miami and 9 of 10 patients at Pittsburgh received HAART therapy before OLT, although 2 of the Pittsburgh patients had their HAART therapy discontinued before OLT because of significant liver dysfunction. The pre-OLT viral loads were undetectable in 13 of 16 patients. The cluster determinant (CD)4 count was less than 200 in 6 patients and greater than 100 in 2 patients before OLT. In all patients, CD4 counts increased above 200 in the post-OLT period. Tacrolimus toxicity associated with the pharmacologic inhibition of cytochrome p450 metabolism caused by protease inhibitors occurred in 6 patients after OLT. Six patients (38%) experienced acute cellular rejection immediately after OLT. Our experience suggests that OLT is effective in selected HIV-positive patients suffering from ESLD. Patient and graft survival was similar to non-HIV-positive patients suffering from the same indications for OLT. Acute cellular rejection was no less frequent that seen in non-HIV-positive patients. Given the complex pharmacologic interactions between the protease inhibitors and tacrolimus, careful monitoring, and attention is required to prevent toxicity or underdosing.
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PMID:Orthotopic liver transplantation in patients with human immunodeficiency virus and end-stage liver disease. 1261 20

The incidence of Kaposi's sarcoma (KS) in transplant recipients is 400-500 times greater than that in the general population, and is rising within the transplant population. In this study, between March 1983 and December 2001, 1055 cases were recorded where KS developed in 18 patients (1.7%) who were treated with AZA + CsA + MP, MMF + CsA + MP, MMF + Tac + MP, CsA + MP, or AZA + MP therapy (AZA, azathioprine; CsA, cyclosporine A; MP, methylprednisolone; MMF, mycophenolate mofetil; Tac, Tacrolimus). In the present study, 18 renal transplant recipients who developed KS and were followed and analyzed. Analysis revealed that a continuous state of immunodeficiency is important for the development of KS. Prognosis in patients with KS limited to the skin is favorable, while visceral involvement is associated with high mortality. Transplant function is well preserved in most of the cases. The association, previously described, between human herpesvirus 8 (HHV8) and transplant-associated KS also exists in the studied population.
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PMID:Clinicopathological aspects of 18 Kaposi's sarcoma among 1055 Greek renal transplant recipients. 1515 55

Large scale screening for neuroprotective drugs for peripheral neuropathies requires development of a high throughput system that is reliable and reproducible. Currently most accurate outcome measures of axonal degeneration are based on time-consuming, laborious measurement of morphological changes in neurites. In order to improve on the scalability of the screening procedure we developed a real-time RT-PCR based method of gene expression that correlates very well with morphological measures of neuritic degeneration. We examined the changes in GAP-43 expression in primary dorsal root ganglion (DRG) neurons in vitro with exposure to a zalcitabine (ddC), an antiretroviral drug that causes neuropathy in human immunodeficiency virus (HIV)-infected individuals, with and without FK506, an immunophilin ligand with neuroprotective and neuroregenerative properties. Similar to morphological measures of neuritic degeneration, in ddC-treated cultures there was a reduction in the expression of GAP-43 mRNA. This was prevented, in a dose-dependent manner, by co-administration of FK506. This assay, performed in a 96-well format, can easily be scaled for high throughput screening (HTS) using robotic systems.
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PMID:The use of GAP-43 mRNA quantification in high throughput screening of putative neuroprotective agents in dorsal root ganglion cultures. 1518 71

The whole blood concentration of tacrolimus is required for therapeutic drug monitoring of this immunosuppressive drug. Abnormal tacrolimus levels affect its efficacy or toxicity, leading to changes in its dosage. Here, we report analytical interference in the affinity column-mediated immunoassay tacrolimus method on the Xpand autoanalyzer in a kidney transplant human immunodeficiency virus-infected patient. Tacrolimus concentrations obtained by affinity column-mediated immunoassay are 3- to 7-fold higher than measurements with the enzyme multiplied immunoassay technique assay. The cause of this interference remains unknown. However, it would be necessary to identify this type of interference to measure tacrolimus concentration with another method to avoid analytical error, which may lead to a poor clinical outcome.
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PMID:Falsely elevated whole blood tacrolimus concentrations due to interference in an affinity column-mediated immunoassay method on Xpand dimension. 1921 46


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